Neutrophil phenotypes and functions in cancer

Neutrophils are the first responders to infection and inflammation and are thus a critical component of innate immune defense. Understanding the behavior of neutrophils as they act within various inflammatory contexts has provided insights into their role in sterile and infectious diseases; however, the field of neutrophils in cancer is comparatively young. Here, we summarize key concepts and current knowledge gaps related to the diverse roles of neutrophils throughout cancer progression. We discuss sources of neutrophil heterogeneity in cancer and provide recommendations on nomenclature for neutrophil states that are distinct in maturation and activation. We address discrepancies in the literature that highlight a need for technical standards that ought to be considered between laboratories. Finally, we review emerging questions in neutrophil biology and innate immunity in cancer. Overall, we emphasize that neutrophils are a more diverse population than previously appreciated and that their role in cancer may present novel unexplored opportunities to treat cancer. Acknowledgments This consensus statement is dedicated to our esteemed colleagues, Zena Werb and Paul S. Frenette, who attended and participated in the Banbury Center meeting and encouraged a collective effort by attendees to write this report. Both made significant contributions to ideas and discussions that are represented here. The Banbury Center meeting was organized by M. Egeblad, P. Kubes, K.E. de Visser, R. Leshan, and Banbury Center staff. The meeting was supported financially by Cold Spring Harbor Laboratory Northwell Health Affiliation. The funder had no involvement with the writing of this consensus statement. D.F. Quail acknowledges funding from the Canadian Institutes of Health Research (PJT-159742, PJT-178306), Terry Fox Research Institute, and Tier II Canada Research Chair. B. Amulic acknowledges funding from the Medical Research Council (MR/R02149x/1). M. Aziz acknowledges funding from the National Institutes of Health (NIH; R01GM129633). B.J. Barnes acknowledges funding from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR065959-01) and Department of Defense (CDMRP LRP W81XWH-18-1-0674). E. Eruslanov acknowledges funding from the NIH National Cancer Institute (NCI; R01CA187392) and the Department of Defense (CDMRP W81XWH-15-1-0717). Z.G. Fridlender acknowledges funding from the the Israel Science Foundation (grant number 1708/20) and the Sasson and Luisa Naor Fund. H.S. Goodridge acknowledges funding from the NIH National Institute of Allergy and Infectious Diseases (R01AI134987). Z. Granot acknowledges funding from the Israel Science Foundation Grant 405/18, the Israel Cancer Research Fund, the Deutsche Forschungsgemeinschaft, and the Rosetrees Trust. A. Hidalgo acknowledges funding from FET-OPEN (861878) from the European Commission; the Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministerio de Ciencia e Innovacion and the Pro-CNIC Foundation. M.J. Kaplan acknowledges funding from the Intramural Research Program of the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIAAR041199). I. Malanchi acknowledges funding from the European Research Council grant (ERC CoG-H2020-725492) and from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001112), the UK Medical Research Council (FC001112), and the Wellcome Trust (FC001112). T. Merghoub acknowledges funding from the NIH/NCI Cancer Center Support Grant (P30 CA008748/NCI R01 CA056821), Swim Across America, Ludwig Institute for Cancer Research, Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, and Parker Institute for Cancer Immunotherapy. E. Meylan acknowledges funding from the Swiss National Science Foundation (310030_179324) and Fonds de la Recherche Scientifique (MISU F.6003.22). M.J. Pittet acknowledges funding from the Institut Suisse de Recherche Experimentale sur le Cancer Foundation, Ludwig Cancer Research, and the NIH (P01CA240239, R01CA218579). I.A. Udalova acknowledges funding from the Wellcome Trust Investigator Award (209422/Z/17/Z). T.K. van den Berg acknowledges funding from Byondis BV, the Dutch Ministry of Health, and the Dutch Cancer Society (10300). D.D. Wagner acknowledges funding from the NIH National Health, Lung and Blood Institute (R35HL135765). P. Wang acknowledges funding from the NIH National Institute of General Medical Sciences (R35GM118337). A. Zychlinsky acknowledges funding from the Max Planck Society. K.E. de Visser acknowledges funding from the Dutch Cancer Society (KWF10623, KWF10083, and KWF13191), Oncode Institute, and the Netherlands Organization for Scientific Research (NWO-VICI 91819616). M. Egeblad acknowledges funding from the Department of Defense, Congressional Directed Medical Research Program (W81XWH2010753). P. Kubes acknowledges funding from the Canadian Institutes of Health Research. Sí